Cystic neoplasms of the pancreas: Epidemiology, clinical features, assessment, and management

Serous cystadenomas

SCAs were first characterized by Compagno and Oertel in 1978 as microcystic and glycogen rich. Their paper in 1978 was a seminal article that clearly distinguished SCAs from mucinous cysts (MCNs and IPMNs; see Chapter 59 ). ^, Around half of patients with SCAs are found incidentally. In symptomatic patients, abdominal pain, palpable mass, and weight loss are the most common manifestations. These symptoms are usually related to the mass effect of the cyst. Jaundice, because of bile duct compression, is infrequent. Of note, SCAs can be associated with von Hippel-Lindau (VHL) disease. SCAs were reported between 2.7% and 9.5% of patients with VHL disease. In these patients, SCAs are generally diagnosed at a younger age (25 years) compared with the general population and have a benign course.

SCAs presents with morphologic varieties including microcystic, macrocystic (or oligocystic), mixed microcystic and macrocystic, and solid SCA. Grossly, these cysts are characterized by septations and thick fibrous walls and have what appear to be innumerable small cysts containing clear thin fluid. Microcystic SCAs often have a classic honeycomb appearance and a calcified central scar with or without hemorrhage. The septa may centrally coalesce into a characteristic “stellate scar” with or without calcification itself, which is pathognomonic for SCAs. These lesions may also be oligocystic (single large cyst) in appearance on imaging and, if so, are very difficult to distinguish from mucinous lesions. Because of the fibrous nature of this lesion, a solid component is often visualized and, if noted in the presence of the other characteristic findings of SCA, should not be considered as concerning for invasive carcinoma.

SCAs are generally considered benign lesions. Serous cystadenocarcinoma is extremely uncommon and usually reported as case reports. Currently, about 30 cases of serous cystadenocarcinoma have been reported in the literature. Many of these case reports describe the “malignant” SCA as locally invasive, whereas only 14 of 30 cases (46.6%) had evidence of metastasis. Despite the presence of metastasis, long-term prognosis was excellent in these patients. ^, It appears that the true incidence of invasive carcinoma within SCAs is much less than 1%. In a multinational study from 23 countries including 2622 patients with SCAs, 61% underwent surgical resection with only 0.1% of patients diagnosed with serous cystadenocarcinoma. The more common problem caused by these lesions is local invasion resulting in symptoms such as early satiety, obstructive jaundice, and pain. Intuitively, large lesions are more likely to produce symptoms; several factors such as female gender, older age of patients when first detected, and larger cyst size (>10 cm) were associated with the risk of invasive carcinoma. ^,

Mucinous cystic neoplasms

MCNs are mucin-producing cystic tumors that lack communication with the pancreatic duct and contain mucin-producing columnar epithelium. An ovarian-like stroma surrounding the columnar epithelium is considered a pathognomonic finding and is the presumed reason that MCNs are almost exclusively found in females (see Chapter 59 ). The ovarian stroma is a characteristic that pancreatic MCNs share with mucinous cysts found in the ovary and the liver. MCNs have been classified separately from IPMNs by WHO since 1996. Pancreatic MCNs are most commonly found in the body and tail and can range in size from small (2 cm) to large (25 cm). Many MCNs are discovered incidentally, but patients may have symptoms such as abdominal pain, nausea or vomiting, back pain, recurrent pancreatitis, or rarely jaundice. ^,

Any macrocystic lesion in the distal pancreas of a female patient should be considered highly suspicious for MCN. These lesions are often unilocular but may contain septa within the primary lesion. When these lesions are multilocular, they are typically macrocystic, in contrast to SCAs (microcystic). These lesions may also have peripheral “eggshell” calcifications that are best demonstrated on the noncontrast phase of CT imaging. Any evidence of mural nodularity in these lesions is considered concerning for invasion. Upon gross inspection, these tumors are round with a smooth surface and fibrous pseudocapsule.

These tumors, in contrast to SCAs, have a risk for harboring invasive carcinoma. Rates of invasive disease range from 10% to 50%, which may be an underestimate because both benign and malignant epithelium may coexist within the same cyst. Only an extensive pathologic evaluation may detect both entities and is critical for an accurate diagnosis. Clinical factors that increase the risk of invasive carcinoma in MCNs are not well characterized. In a multicenter analysis of data from eight academic centers in the United States, the overall rate of invasive carcinoma in MCN lesions reported up to 15%. Factors associated with the risk of invasive carcinoma were male gender, pancreatic head and neck location, larger MCN, mural nodules, and duct dilation. Because of the rarity of these lesions, the natural history is not well defined. The 5-year disease-specific survival for patients with invasive carcinoma was estimated between 57% and 64%. ^,

Intraductal papillary mucinous neoplasms

IPMNs are epithelial tumors that arise from the main pancreatic duct or the branch ducts, causing ductal dilation from mucin production. It is a recently described entity and was first classified into a unified diagnosis by WHO in 1996. Because of the increasing use of high-quality cross-sectional imaging, the identification of asymptomatic cystic lesions of the pancreas has increased, and a significant percentage of patients with incidentally discovered cysts will have IPMNs. In contrast to MCNs, IPMNs occur equally in men and women and are more often found in older individuals, with the peak incidence between 50 and 70 years. Among cystic neoplasms diagnosed in large series, IPMNs represent approximately 15% to 30% of all lesions. ^{, ,} Because of the recent evolution in the understanding of IPMN, many early reports likely included a mixture of patients with IPMN and MCN and should be interpreted with caution.

IPMN is believed to be a process that involves the entire pancreas; however, radiographically detectable disease may present as involving the main duct alone, branch ducts alone, or both (mixed variant). The main-duct IPMN (MD-IPMN) is characterized by diffuse or segmental dilatation of the main pancreatic duct (>5 mm) without other reasons for obstruction. Cysts that have communication with the main pancreatic duct without significant dilation of the main pancreatic duct are defined as branch-duct IPMN (BD-IPMN). They may be unilocular, multilocular, and have septations or mural nodularity. In the absence of septations, mural nodules, or a solid component, BD-IPMNs may be radiographically and endoscopically indistinguishable from pancreatic retention cysts, MCNs, small cystic endocrine tumors, or even pancreatic pseudocysts. IPMN is classified as mixed-IPMN when branch-duct dilation is associated with main-duct dilation (main pancreatic duct > 5 mm).

This radiographic classification of IPMN into MD-IPMN, BD-IPMN, or the mixed variant has formed the backbone of the management paradigm of IPMN because the radiographic subtype is one of the strongest predictors of high-grade dysplasia or invasive cancer (see Chapter 17 ). As many as 60% of MD-IPMNs are malignant (high-grade dysplasia and invasive cancer), and as many as 45% have invasive adenocarcinoma, thus forming the basis of the recommendation that, in general, patients with MD-IPMN should undergo resection. ^, Invasive carcinoma or high-grade dysplasia is reported in 12% to 30% of patients who undergo resection for BD-IPMN. ^, Series of patients who have undergone resection for mixed IPMN have generally reported rates of invasive carcinoma or high-grade dysplasia in between those of BD-IPMN and MD-IPMN (see Chapter 59 ).

IPMN can also be classified based on cellular morphology as gastric, intestinal, pancreatobiliary, or oncocytic. This classification is based on histologic appearance, mucin (MUC) gene expression, and tissue architecture. Each subtype exhibits a particular risk of invasive carcinoma. The gastric-type papillae are often mingled with tubular glands resembling pyloric glands. Intestinal-type IPMNs have villous papillae consisting of tall columnar cells with pseudostratified cigar-shaped nuclei and basophilic cytoplasm with variable amounts of apical mucin. Pancreatobiliary-type IPMNs have complex branching papillae consisting of columnar cells with marked atypical nuclei and neutral or basophilic cytoplasm. Finally, the oncocytic-type has arborizing papillae consisting of cells with enlarged round nuclei and eosinophilic cytoplasm secondary to an abundance of mitochondria. ^,

Histologically, the mucosa of IPMN can express a range of dysplasia. IPMNs were graded based on the revised classification system and recommendations from the Baltimore consensus into low-grade dysplasia, high-grade dysplasia, or invasive carcinoma. Multiple degrees of dysplasia can coexist in a resected specimen of IPMN, and generally pathologists will report this as the highest grade of dysplasia in the resected lesion (see Chapter 59 ).